ROLE OF ATAXIA TELANGIECTASIA IN CHECKPOINT CONTROL

放射治疗是癌症治疗的一个重要而有效的组成部分，但 它的成功在很大程度上取决于肿瘤细胞对辐射的敏感性。作为 肿瘤细胞的遗传组成是决定 辐射抗性，了解生物化学和分子途径 正常细胞和肿瘤细胞决定它们是否应该对DNA进行损伤 以及在细胞周期中的进展，或者它们应该经历细胞凋亡 在开发更有效的方法来处理无线电方面是至关重要的- 耐药肿瘤。我们研究的长期目标是确定 指定辐射诱导DNA损伤检查点的分子途径 控制力。能够识别和操纵这一系统的关键组件 系统应允许开发更有效的放射治疗 策略和提供可靠的标记物来预测肿瘤对 放射治疗。 这项提议的目标是描述分子和 ATM蛋白的生化功能(共济失调毛细血管扩张症突变) 及其相关蛋白质作为了解分子的一步 人类细胞中检查点控制的机制。使用高度特定的 ATM抗体，我们证明了辐射诱导的一种激酶活性 与自动取款机紧密相关。我们将通过以下方式来研究生化机制 哪种辐射可激活ATM激酶，并表征可 与自动取款机配合使用，以激活检查点控制。我们有 确定了四种与自动取款机相关的候选蛋白质，我们建议 为了研究这些相互作用的分子基础作为DNA的函数 损伤和细胞周期控制。生化分析中的滞留分析 而ATM的分子蛋白质应该以显著的方式做出贡献 以确定分子对辐射诱导的DNA损伤的反应。

Radiation is an important and effective component of cancer therapy but its success relies largely on the radio-sensitivity of tumor cells. As the genetic composition of a tumor cell is one of the major determinants of radio-resistance, understanding the biochemical and molecular pathways in normal and tumor cells that determines whether they should the DNA damage and progress through the cell cycle or that they should undergo apoptosis is paramount in developing more effective ways to deal with radio- resistant tumors. The long-term goal of our research is to determine the molecular pathways that specify radiation-induced DNA damage checkpoint control. The ability to identify and manipulate key components of this system should allow for development of more effective radiotherapeutic strategies and provide reliable markers for predicting tumor response to radio-therapy. The goals of this proposal are to characterize the molecular and biochemical functions of the ATM protein (ataxia telangiectasia mutated) and its associated proteins as step towards understanding the molecular mechanism of a checkpoint control in human cells. Using highly specific ATM antibodies, we show that radiation induces a kinase activity that is tightly associated with ATM. We will examine the biochemical mechanism by which radiation activates ATM kinase as well as characterize proteins that act in conjunction with ATM to activate checkpoint control. We have identified four candidate proteins that associate with ATM and we propose to examine the molecular basis of these interactions as a function of DNA damage and cell cycle control. The detained analysis of the biochemical and molecular proteins of ATM should contribute in a significant way towards defining the molecular response to radiation induced DNA damage.